The emergence of multidrug resistant microbial infections (e.g., bacterial infections) has led to a serious global crisis. Almost every class of antibiotic that has been introduced into the clinic has been met with the development of drug resistant bacteria (A. E. Clatworthy, E. Pierson, and D. T. Hung, Nat. Chem. Biol., 2007, 3, 541-548; K. Lewis, Nat. Rev. Drug Discov., 2013, 12, 371-387). Despite the growing need for new antimicrobial agents, many pharmaceutical companies have abandoned their antimicrobial discovery programs as the anticipated success with target-based, high-throughput screening (HTS) campaigns has yet to be realized (K. Lewis, Nat. Rev. Drug Discov., 2013, 12, 371-387; S. J. Projan, Curr. Opin. Microbiol., 2003, 6, 427-430; E. D. Brown and G. D. Wright, Chem. Rev., 2005, 105, 759-774; D. J. Payne, M. N. Gwynn, D. J. Holmes, and D. L. Pompliano, Nat. Rev. Drug Discov., 2007, 6, 29-40). The health care emergency that has resulted from drug resistant microbial infections has been gaining momentum over the past four decades as only two new classes of antibiotics have been introduced into the clinic (K. Lewis, Nat. Rev. Drug Discov., 2013, 12, 371-387; E. D. Brown and G. D. Wright, Chem. Rev., 2005, 105, 759-774).
A wide range of microorganisms produce potent antibiotics as agents of microbial warfare and competition. As a result, the large majority of the antibiotic arsenal is based on such natural products discovered in the antibiotic golden era between the 1940s and 1960s (e.g., penicillin, streptomycin, erythromycin, tetracycline, vancomycin) or their synthetic derivatives (Lewis, Nat. Rev. Drug Discov., 2013, 12, 371-387). In fact, very few clinically useful treatment options for microbial infections have been developed from purely synthetic origins (e.g., sulfonamides, quinolones, oxazolidinones).
In addition to infections resulting from planktonic bacteria, biofilms also play a key role in pathogenesis. The NIH has stated that bacterial biofilms are associated with up to 80% of all bacterial infections. Biofilms are notorious for their resistance to conventional antibiotic treatments. Currently, there is a desperate need for clinically useful anti-biofilm agents as there are no FDA-approved drugs that effectively target biofilm machinery. Innovative antimicrobial strategies are needed to meet the biomedical challenges of microbial infections, especially those resulting from multidrug resistant microbial infections and pathogenic bacterial biofilms.